INTRODUCTION:

The process of developing a novel, more effective medicine delivery method is arduous and complex. In this field, human labor has mostly been driven by necessity¹. The most common and favored approach to medication distribution has traditionally been oral administration because it provides the largest active surface area compared to all other drug delivery methods, and it's also the most affordable and practical².

The primary objective of creating a sustained release dosage is to extend the medication's release and sustain an approximately linear drug level for a set amount of time to ensure the medication has the fewest negative effects and is most effective³. Micro particles with a spherical diameter measured in micrometers make up the microsphere. Drug microspheres that float show signs of a continuous and extended therapeutic impact while lowering dosage frequency^4,5.

Drugs with a short half-life and easy absorption from the gastrointestinal tract (GIT) must be taken often since they are rapidly removed from the bloodstream. In an effort to circumvent this problem, oral sustained-controlled release formulations have been created with the goal of releasing the medication gradually into the GIT and keeping an effective drug concentration in the serum for an extended amount of time⁶. Controlling the gastric residence time (GRT) with gastro retentive dosage forms is one of the most practical methods for attaining a longer and consistent drug delivery profile in the GI tract. Because GRDF can stay in the stomach area for several hours, the medications' GRT can be considerably extended. Extended stomach retention increases the solubility, lowers drug waste, and increases bioavailability of medications that are less soluble in high pH environments. It can also be used to deliver drugs locally to the stomach and the first few inches of the small intestine. Thus, GRDFs will provide us novel and significant therapeutic alternatives⁷.

Basic Physiology:

1. Anatomy:

Anatomically, the stomach is made up of three parts: the fundus, which is located above the passage of the esophagus into the stomach, the body, or core section, and the antrum, also known as the pylorus. The stomach is an organ that has the ability to store and mix food. The fundus and body portions of the proximal stomach act as a reservoir for materials that have been consumed, whereas the antrum, located in the distal region, is the main site of mixing motions and functions as a pump to facilitate gastric emptying. When on a fast, the stomach is a compressed bag with a 50 ml residual capacity that is partially filled with air and a tiny amount of gastric fluid (pH 1-3).

Figure 1. Schematic view on the anatomy of Stomach

Most medications have very little gastric absorption under physiological settings due to the small surface area (0.1–0.2 m2) of the stomach. Coated in a thick layer of mucus, the absence of villi on the mucosal surface, and the brief duration of most medications' occupancy in the stomach⁸.

2. Dynamics:

Although the process of stomach emptying happens in both the fed and fasting stages, there are notable differences in the motility pattern between them. An inter-digestive series of electrical events that take place in the stomach and small intestine every two to three hours characterizes it when the body is fasting.⁹ This process, known as the migrating myoelectric complex (MMC) or interdigestive myoelectric cycle, is frequently split into four stages.¹⁰

Figure 2 Phases of gastric retention

The average time to go through all four of these phases is between 90 and 120 minutes. Clearing the stomach and small intestine of all indigestible items is the housekeeping function of Phase III. Therefore, if one desires to extend the GI retention duration, any CR gastrointestinal drug delivery system (GIDS) intended to remain during the fasting state should be able to withstand the housekeeping action of phase III. The pattern of contraction shifts from the fasted condition to the fed state following the consumption of a mixed meal. This pattern, which is also referred to as the digestive motility pattern, consists of constant contraction similar to that of phase II fasting. Food particles (less than 1 mm) are reduced in size as a result of these contractions and are then driven in the form of suspension towards the pylorus. The delayed start of MMC during the fed state causes the pace of stomach emptying to slow down.

Advantages of GRDDS:

1. When comparing the administration of non-gastric retentive drug delivery to this method, the bioavailability of therapeutic drugs can be greatly increased, particularly for those that are metabolized in the upper gastrointestinal tract. Many associated factors that are linked to drug absorption and transit in the gastrointestinal tract (GIT) that operate concurrently affect the degree of drug absorption.

2. Sustained release can lead to a flip-flop pharmacokinetics for medications with comparatively short half-lives. It can also permit lower dosage frequency with better patient compliance.

3. They also have an edge over their traditional technique since they can use it to get around the problems caused by the gastric emptying time (GET) and the gastric retention time (GRT). Because their bulk density is lower than that of the stomach fluids, these devices are projected to stay buoyant on the gastrointestinal fluid without influencing the intrinsic rate of employing.

4. Drugs from dosage forms that provide local therapy in the stomach and small intestine can be released from dosage forms more slowly and sustainably with the help of gastro retentive drug delivery. As a result, they are helpful in the treatment of stomach and small intestinal conditions.

5. The use of gastro retentive dosage forms reduces concentration variations and pharmacological effects. As a result, negative effects linked to peak concentrations that are concentration-dependent can be shown. This characteristic is especially crucial for medications with limited therapeutic indexes.

6. By reducing the body's counteractivity, gastro retentive medication administration can increase drug efficiency.

Disadvantages of GRDDS:

1. Unsuitable for medications with a low acid solubility. For instance, phenytoin.

2. Unsuitable for medications in environments that are unstable and acidic. For instance, erythromycin.

3. Medications with a delayed release that irritate the stomach or cause sores. such as NSAIDs and aspirin.

4. Drugs, such as corticosteroids, that absorb specifically in the colon.

5. Medications that the GIT can absorb equally well. Such as nifidipine, dinitrate, and Isosorbide.

Approaches to Gastric Retention:

A wide range of ideas employed a multitude of tactics to enhance the GRT of a certain medicine kind in the stomach¹¹. These are related to:

Low density system:

Low-density/floating systems represent the most sophisticated and thoroughly tested components of gastro retentive dose^12-13. In 1968, Davis became the first institution to embrace the floating system. It is possible to attain a degree of drug bioavailability optimization through selective gastric retention. One novel idea in this regard is the floating medicine delivery system¹⁴. Gastric fluid becomes buoyant due to system. The density of stomach fluid is higher than that of pellets or pills^15-18.

High density systems:

Makes use of the dosage form's density as a tactic to create the retention mechanism. The dose form's density is higher than the gastric fluid near the bottom of the stomach, where the sinking system is still present. The density of the formulation is higher than that of typical stomach content. Density is increased to 1.5–2.4gm/cm³ by the materials. Depending on density, pellets' GI transit time can be prolonged by 5.8 to 24hours. Nevertheless, there is little evidence of this method's effectiveness in humans, and no commercial formulation has been released.

Expandable systems:

The dose form expands in the stomach via expanding or unfolding. Diffusion is typically the cause of swelling. It unfolds because of mechanical form memory^19-21. These systems can grow and remain in the stomach for extended periods of time. Usually, these come in the shape of capsules with a compressed and folded dosage form. In the stomach environment, the dose form expands and the capsule shell disintegrates, preventing it from passing through. Using the appropriate polymer can help achieve controlled and maintained drug distribution.

Bio adhesive or Mucoadhesive systems:

A multi-mechanism process that involves electrical theory, adsoption, wetting, dilation, and fracture theories. The bio adhesive process may be aided by the contact between positively charged polymers and the negatively charged mucosal surface²². By adhering the gastric mucous membrane bio adhesive system, the gastric retention period has been prolonged. The delivery system's adherence to the stomach wall increases bioavailability by extending residence time. Gliadin, carbopol, lecithin, chitosan, polycarbophil, and carboxymethyl cellulose are among the substances that are utilized for mucoadhesion¹⁸. Adhesion to the gut has also been investigated for novel adhesive materials made from synthetic equivalents or bacterium fimbria. Nevertheless, the power of the stomach wall's propulsion is too great for the gastric mucoadhesive to withstand. The constant generation of mucus and diluting of the stomach content is another drawback of this kind of system. Numerous researchers have tested a synergistic technique that combines a bio adhesion system with floating.

Raft forming systems:

When mono- or divalent cations are present, the polymer absorbs water, swells, and forms in situ gel layers that are known as rafts because they float over stomach fluid ^23-24. These systems are designed with gel-forming polymers and effervescent excipients to provide sustained medication delivery. These devices work well to produce a localized effect because they operate as a barrier between the stomach and the oesophagus. Consequently, peptic ulcers and gastric reflux disease can be treated using the device. When these systems come into contact with stomach acid, they expand and produce a cohesive gel that is viscous, which leads to the production of a continuous layer called a raft. Another new invention is the antacid raft forming method, which employs acid neutralizer, sodium bicarbonate, and sodium alginate as gas-generating agents and sodium alginate as a gel-forming polymer. Because of the creation of CO2, which lowers the bulk density of the system, the raft floats on the stomach fluid. For several hours, the raft can float on the gastric fluid and constantly release medication. These rafts are very helpful for dispensing antacid drugs.

Super-porous hydrogel systems:

Super porous hydrogel was introduced as an alternative class of water-absorbent polymer system in 1998. This system's excellent mechanical strength and elastic qualities have made it more and more popular in the controlled-release formulation. Increases in size by up to 100 times as a result of water updating through multiple pores in the capillaries²⁵.

Magnetic systems:

Consists of a medication mixture and a tiny inside magnet. An extracorporeal magnet regulates its location within the stomach. A dosage form in a magnetic system comprises an internal magnet, excipients, and the active medicinal substance²⁶.

Swelling system

When taken to a level that prevents them from passing through the pylorus, certain drug kinds swell. Consequently, the kind of drug is kept in the stomach for an extended period of time. These devices are sometimes referred to as plug-type systems due to their tendency to remain lodged at the pyloric sphincter. For the previous few hours, these polymeric matrices have been working in the stomach cavity, perhaps even during the meal phase. Drugs can be released continuously and under control by selecting a polymer with the appropriate molecular weight and swelling properties.^38-39

Ion-exchange resin systems:

The resin loaded drug complex is created when the drug is placed into the resin; this system can be paired with either floating delivery or bio adhesive systems²⁶. The cationic or anionic water-insoluble cross-linked polymer, often known as resin, is the part of the ion-exchange resin system. It is usually made to release the medication in a regulated way. The qualities of the medicine can be used to select the appropriate resins. Since cationic medications should be released in the stomach in the case of GRDDS, this approach is appropriate for them. As a result, cationic resin is an option. A known drug concentration is blended uniformly for a predetermined amount of time after a certain amount of resin has been added. Adsorbed onto the resin matrix, the drug ions from the solution displace the resin's cations. Resonates are the loaded pharmacological resin complexes.

Key Factors Affecting the Performance of GRDDS:

The effectiveness of gastro retentive dose forms is influenced by a number of factors. These elements fall into three primary categories: Pharmaceutical factors, physiological factors, and pharmacological considerations.

Pharmaceutical factors:

It's critical to comprehend the impact of polymers and excipients on different forms of GRDDS in order to successfully design GRDDS²⁷. For example, in the mucoadhesive system, high mucoadhesion strength polymers like carbopol and hydroxypropyl methylcellulose (HPMC) might be necessary for the mucoadhesive dosage form to be designed successfully. Similarly, polymers with strong swelling capabilities are preferred when using the expandable system. Furthermore, the dose form may also be influenced by the molecular weight, viscosity, and physiochemical characteristics of polymers.

Additionally, the dosage unit's size and shape are crucial ²⁸. According to Garg and Sharma, dosage forms with ring and tetrahedron geometries had longer GRTs than those with other shapes²⁹. The GRT of the dose form is typically proportionately based on the size. Because the dose form's size is greater than the pyloric sphincter diameter (mean, 12.8 ~ 7mm), an increase in size may hinder it from passing through the pyloric antrum in the intestine³⁰. For both low- and high-density systems, the dosage form's density is a crucial consideration. To float in the gastrointestinal environment in low-density systems, the dose forms' density should be less than the gastric fluid's (1.004g/cm³).^31-32

Physiological Factors:

Numerous studies have shown that a range of extrinsic factors can influence the gastric reflux times (GRTs) of medications in the stomach. These factors include the type of meal, frequency of intake, posture, sleep patterns, and calorie content (both caloric density and type of calories)^15,28. Gastrointestinal motility during fasting is indicated by the MMC, which happens every 90–120 minutes¹⁶. Motor action removes undigested food from the stomach at this time. The unit's GRT is very brief if the formulation administration schedule aligns with the MMC's. Nevertheless, when food is present in the stomach, the MMC is halted and housekeeping waves are not produced, which results in an extended GRT^16,18. On the other hand, when lying supine, the non-floating system has a longer GRT than the floating system¹⁴.

Pharmacological Consideration:

GRDDS can be influenced by patient-related characteristics such as age, gender, disease, and emotional state. The scientists showed that compared to men, women had slower stomach emptying times³³. The longer GRT in females compared to males may be explained by hormonal effects. According to a different study, men secreted more stomach acid than women³⁴. Similarly, the patient's age has an impact on the GRT. Patients who are older than those who are younger have a longer GRT³⁵. The GRT of the dose form may also be impacted by the patient's condition. For example, individuals with Parkinson's disease typically experience constipation in addition to a prolonged GRT³⁶. Similarly, there is a 30-to 50% reduction in stomach emptying in diabetic patients³⁷. GRDDS may also be impacted by a patient's emotional state. According to a report, individuals suffering from sadness showed a drop in their stomach emptying rate, whereas those experiencing anxiety showed an increase in their rate²⁸.

Future perspectives of GRDDS:

One of the biggest problems facing the pharmaceutical business is the GRT of the typical dosage form, particularly for medications that are absorbed from the upper intestine. The disadvantages of the standard dose form will be mitigated by the development of GRDDS, while more research is required to address these issues. Numerous researches on GRDDS, including those involving floating, expandable, and mucoadhesive systems, have been conducted to date using the single system approach.

The following are the future perspectives of GRDDS:

1. Improved bioavailability of drugs: GRDDS can be utilized to increase a drug's bioavailability by shielding it from enzymes or stomach acid degradation. Osmotic, mucoadhesive, and floating systems can all be used for this.

2. Prolonged medication release: By keeping the drug from being released too soon, GRDDS can be utilized to prolong the drug's release period. Both magnetic and osmotic methods can be used for this.

3. Personalized medication administration: Drugs can be administered to a particular spot in the stomach using GRDDS. Magnetic or bio adhesive methods can be used for this.

4. Reduced side effects: By delivering medication to a specific area of the stomach or preventing it from being absorbed too quickly, GRDDS can be used to lessen the negative effects of medication.

5. Increased adherence from patients: Patient compliance may be increased by making GRDDS easier to take and more convenient. For instance, GRDDS can be produced as easier-to-swallow chewable pills or capsules.

GRDDS are a cutting-edge technology that shows great promise for enhancing the management of numerous illnesses. GRDDS has the potential to completely change how medications are absorbed into the stomach with more study and development.

There is a bright future for GRDDS. GRDDS have the potential to completely change how medications are given to the stomach and enhance the treatment of a variety of illnesses with more study and development.

Research on the creation of GRDDs is a promising field. GRDDs have the potential to more safely and effectively deliver a greater variety of medications with further development.

CONCLUSION:

A comprehensive analysis of many published works and in-depth research on commercial products lead to the conclusion that no single gastro-retentive system can be identified as the most appropriate for any given drug candidate. However, the bulk of them have demonstrated a number of benefits of GRDDS for patients. The therapeutic efficacy of medications with limited absorption windows, high solubility at acidic pH, and instability at alkaline pH could be greatly enhanced by GRDDS. A comprehensive comprehension of the stomach's anatomy and physiological condition, along with research on the effects of formulation and process variables on dosage form quality, are essential for the effective design of GRDDS. The literature has reported on a number of GRDDS, including bio/mucoadhesive, magnetic, low- and high-density systems; however, further research is still needed to determine their therapeutic importance. From a pharmacological perspective, GRDDS may need to concentrate on a combination strategy in the future to improve product quality. Every day, the FDDS gives rise to greater optimism for a bright future.

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Received on 03.04.2024 Modified on 08.06.2024

Res. J. Pharma. Dosage Forms and Tech.2024; 16(3):293-298.

DOI: 10.52711/0975-4377.2024.00046